Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.

TitleMutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.
Publication TypeJournal Article
Year of Publication2020
AuthorsCharif, M, Chevrollier, A, Gueguen, N, Bris, C, Goudenège, D, Desquiret-Dumas, V, Leruez, S, Colin, E, Meunier, A, Vignal, C, Smirnov, V, Defoort-Dhellemmes, S, Bouvet, IDrumare, Goizet, C, Votruba, M, Jurkute, N, Yu-Wai-Man, P, Tagliavini, F, Caporali, L, La Morgia, C, Carelli, V, Procaccio, V, Zanlonghi, X, Meunier, I, Reynier, P, Bonneau, D, Amati-Bonneau, P, Lenaers, G
JournalNeurol Genet
Date Published2020 Jun

Objective: To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations.

Methods: Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI.

Results: We identified 7 and 8 new heterozygous pathogenic variants in and . Both genes encode for mitochondrial matricial AAA (m-AAA) proteases, initially involved in recessive hereditary spastic paraplegia type 7 (HSP7) and dominant spinocerebellar ataxia 28 (SCA28), respectively. Notably, variants in that result in DOA are located in different domains to those reported in SCA28, which likely explains the lack of clinical overlap between these 2 phenotypic manifestations. In comparison, the variants identified in DOA are interspersed among those responsible for HSP7 in which optic neuropathy has previously been reported.

Conclusions: Our results position and as candidate genes to be screened in DOA and indicate that regulation of mitochondrial protein homeostasis and maturation by m-AAA proteases are crucial for the maintenance of optic nerve physiology.

Alternate JournalNeurol Genet
Citation Key10.1212/NXG.0000000000000428
PubMed ID32548275
PubMed Central IDPMC7251510